1. Field of the Invention
The present invention relates to oral peptide pharmaceuticals where the active compounds include a plurality of amino acids and at least one peptide bond in their molecular structures, and to methods of quickly providing good bioavailability of such peptide active compounds when administered orally.
2. Description of the Related Art
Numerous human hormones, neurotransmitters and other important biological compounds have peptides as a substantial part of their molecular structures. Many diseases respond positively to raising the level of these peptide compounds in patients. Therapeutically effective amounts of such biologically relevant peptides may be administered to patients in a variety of ways. However, as discussed further below, oral administration, which is the preferred method, is very difficult with this type of active compound.
Salmon calcitonin, for example, is a peptide hormone which decreases uptake of calcium from bone. When used to treat bone-related diseases and calcium disorders (such as osteoporosis, Paget's disease, hypercalcemia of malignancy, and the like), it has the effect of helping maintain bone density. Many types of calcitonin have been isolated (human calcitonin, salmon calcitonin, eel calcitonin, elkatonin, porcine calcitonin, and chicken calcitonin). There is significant structural non-homology among the various calcitonin types. For example, there is only 50% percent identity between the amino acids making up human calcitonin and those making up salmon calcitonin. Notwithstanding the difference in molecular structure, salmon calcitonin may be used in the human treatment of the calcitonin-responsive diseases discussed above.
Peptide pharmaceuticals used in the prior art frequently have been administered by injection or by nasal administration. Insulin is one example of a peptide pharmaceutical frequently administered by injection. However, injection and nasal administration are significantly less convenient, and involve more patient discomfort than, for example, oral administration. Often this inconvenience or discomfort results in substantial patient noncompliance with a treatment regimen. The more preferred oral administration tends to be problematic, however, because peptide active compounds are very susceptible to degradation in the stomach and intestines. Thus, there is a need in the art for more effective and reproducible oral administration of peptide pharmaceuticals like insulin, salmon calcitonin and others discussed in more detail herein.
Proteolytic enzymes of both the stomach and intestines may degrade peptides, rendering them inactive before they can be absorbed into the bloodstream. Any amount of peptide that survives proteolytic degradation by proteases of the stomach (typically having acidic pH optima) is later confronted with proteases of the small intestine and enzymes secreted by the pancreas (typically having neutral to basic pH optima). Specific difficulties arising from the oral administration of a peptide like salmon calcitonin involve the relatively large size of the molecule, and the charge distribution it carries. This may make it more difficult for salmon calcitonin to penetrate the mucus along intestinal walls or to cross the intestinal brush border membrane into the blood. These additional problems may further contribute to limited bioavailability.
Oral dosage forms which at least partially surmount many of the difficulties described above are disclosed and claimed in U.S. Pat. Nos. 5,912,014 and 6,086,918 to Stern et al., issued Jun. 15, 1999 and Jul. 11, 2000, respectively, which are incorporated herein by reference. Both patents describe peptide dosage formulations which target release of the peptide to the intestine and which enhance bioavailability by administering the peptide in an oral dosage formulation which comprises, in addition to the peptide, at least one pharmaceutically acceptable pH-lowering agent and at least one absorption enhancer effective to promote bioavailability of the peptide. The dosage formulation is, moreover, coated with an enteric coating capable of conducting the peptide, the absorption enhancer and the pH-lowering agent through a patient's stomach, while protecting the peptide from degradation by stomach proteases. Thereafter, the coating dissolves and the peptide, absorption enhancer and pH lowering agent are released together into the intestine of the patient.
In certain instances, however, the condition to be treated by the oral peptide would benefit from more rapid remediation than that provided by the relatively slow dissolution of an enteric coating and related release of the active component(s) within the intestine. One particular example of a condition which benefits from such rapid remediation involves the area of pain relief, where the speed with which such relief is achieved is obviously an important, if not critical, factor to a patient. Furthermore, it is not always required that the active peptide agent(s) be transported all of the way through the stomach and into the intestine. That is, in the case of certain peptide agents, including but not limited to various pain-relievers, it may be most efficacious for absorption of the active agent to occur prior to entry of the formulation into the intestine, e.g., as the material passes down the esophagus or when it is within the patient's stomach. Under such circumstances, while oral bioavailability is still a factor to be considered, patients and/or clinicians may be willing to accept a limited reduction in bioavailability if such reduction is balanced by a corresponding increase in the speed of absorption, and thus of action, by the active agent(s) contained within the formulation.
There has thus been a long-felt need for an oral peptide formulation which is capable of more rapid therapeutic action, i.e, in contrast to the formulations described in the '014 and '918 patents discussed above, while still providing a desirable degree of bioavailability.